In 1954 Max Delbrück published "On the Replication of
Desoxyribonucleic Acid (DNA)" to question the semi-conservative DNA
replication mechanism proposed that James Watson and Francis Crick had
proposed in 1953. In his article published in the Proceedings of the
National Academy of Sciences, Delbrück offers an alternative DNA
replication mechanism, later called dispersive replication. Unlike other
articles before it, "On the Replication" presents ways to experimentally
test different DNA replication theories. The article sparked a debate in
the 1950s over how DNA replicated, which culminated in 1957 and 1958
with the Meselson-Stahl experiment supporting semi-conservative DNA
replication as suggested by Watson and Crick. "On the Replication"
played a major role in the study of DNA in the 1950s, a period of time
during which scientists gained a better understanding of DNA as a whole
and its role in genetic inheritance.

"On the Replication" was Delbrück's
response to two 1953 articles by Watson and Crick concerning DNA. Prior
to the Watson-Crick publications, scientists had determined that genes,
which are the biological factors that control heritable traits, are
comprised of DNA. However, the physical structure of DNA remained
unknown. In addition, scientists did not know how the properties of DNA
translated into the passing of genetic information from one cell to
another. Watson and Crick addressed those questions in their article.

In
their first 1953 article, Watson and Crick described their proposed
structure of DNA. They described DNA as a double helix that contains two
long, helical molecular strands. The DNA strands consist of a backbone
with individual molecular units called bases attached to the backbone.
Like the rungs of a ladder, in Watson-Crick DNA the DNA bases point
inward so that the base of one strand joins with the base of the other,
thereby providing the connecting points between the two DNA strands.
Each DNA base has a specific partner meaning that each base only pairs
with one other type of base. Therefore, according to Watson and Crick,
by knowing the identity of the bases on one DNA strand one could
determine the bases of the other strand. Joined at the bases, the DNA
strands coil around each other along a vertical axis like two pieces of
rope. The strands also have a beginning and an end and each run in
opposite directions, so that the beginning of one DNA strand lines up
with the end of the other. As of 2017, Watson and Crick's DNA structure
remains the accepted structure for DNA.

In "On the Replication,"
Delbrück did not contest the structure of DNA that Watson and Crick had
proposed, but instead he questioned the replication mechanism Watson and
Crick proposed in a second article. In their second article, Watson and
Crick proposed what later became known as semi-conservative DNA
replication. According to Watson and Crick, because each strand of DNA
contained bases that corresponded to the other strand, the strands
themselves could serve as individual templates for self-replication.
Watson and Crick claimed that during replication, the two strands of DNA
untwisted completely and separated, each strand serving as a parent
template on which new, daughter DNA strands are constructed. In their
article, Watson and Crick acknowledged the issue of the strands getting
tangled when uncoiled, but they dismissed the problem as something that
could be overcome.

Delbrück, a researcher at the California Institute of
Technology in Pasadena, California, addressed the problem of DNA strands
tangling during replication with his 1954 article, "On the Replication
of Desoxyribonucleic Acid (DNA)." Delbrück was a scientist educated in
physics. However, when he published his article in 1954, Delbrück
studied biology in search of fundamental laws that governed gene
replication within basic organisms. Following the publication of Watson
and Crick's articles in 1953, Delbrück wrote to Watson about how he
thought the untwisting of DNA strands posed a problem for replication.
He hypothesized different alternate replication mechanisms before
settling on the one he wrote about in 1954 called dispersive
replication.

In "On the Replication," Delbrück details his dispersive
replication model and experimental designs to test that model, along
with the logic and reasoning behind both. The six-page article begins
with a description of the Watson-Crick model of DNA and DNA replication.
Delbrück subsequently calls the model into question and proposes
multiple alternative theories before settling on his favored mechanism,
dispersive replication. Using diagrams and illustrations as aids,
Delbrück details his model and concludes how different aspects of his
mechanism could yield experimental results distinguishing the model from
others. "On the Replication" ends with a brief summary and list of
references.

Delbrück opens his article with a description of the
Watson-Crick model of DNA and the replication mechanism that Watson and
Crick suggested. In summarizing Watson-Crick DNA, Delbrück highlights
how DNA bases function like a genetic code for heritable traits and how
those bases are added sequentially during DNA replication. Delbrück then
states that his main issue with Watson and Crick's replication mechanism
is that their mechanism requires DNA strands to separate.

Delbrück
describes three ways DNA strands could separate before replication. In
the first way, one of the DNA strands is pulled up while the other is
pulled down, meaning that the two strands slide past each other and
apart. The DNA strands are pulled apart from end to end so that the
strands slide past each other vertically. In the second way, the DNA
strands untwist as suggested by Watson and Crick. Delbrück writes that
he rejects both of those hypotheses for how DNA strands separate because
the mechanisms are inelegant and therefore inefficient.

Instead,
Delbrück discusses in more detail a third way by which DNA strands could
separate. According to Delbrück, DNA strands could also separate through
a complex interaction of certain breaks and reunions at each interlock
of the coil formed by the DNA strands. One strand could break along its
backbone before each twist of the double helix, where the strands would
normally get caught. The break in one strand provides a gap for the
other strand to pass through, thereby avoiding tangling. The gap would
then be resealed. Or, both strands break along their backbones at each
twist. The segments below the breaks would then cross over each other in
such a way that the twist is unwound. Lastly, each strand would join
with the part of the opposing strand above the break, leaving the
strands uncoiled. Delbrück argues that both of those processes are
unfavorable. If only one strand breaks, the symmetry of DNA that is
essential to the molecule's stability would be disrupted. If both
strands broke at the same point and crossed over, they would join
opposing strands in the wrong direction, because the strands run in
opposite directions to begin with. Therefore, Delbrück concludes that
DNA strands cannot separate prior to replication. Instead, Delbrück
suggests that the separation of DNA strands and DNA replication occur
simultaneously through a method he describes in the next part of his
article.

In the next portion of the article, Delbrück provides a
description of his replication mechanism, later called dispersive
replication, in which DNA strands replicate and separate at the same
time. The mechanism Delbrück proposes is a modification of the breaks
and reunions method he suggests earlier in his article. Delbrück
considers a case in which replication begins while the two DNA strands
are still twisted together. Between each interlock of the DNA double
helix, the DNA strands can pull apart slightly without fully separating,
forming a bubble. Though not mentioned by Delbrück, the same can occur
between two wound pieces of rope. In the gap formed between the DNA
strands, Delbrück states that the replication of daughter strands can
begin at each parent DNA strand. Delbrück describes that the replication
continues until the assembling daughter strands meet an interlock of the
parent helix. At that point, the parent strands each break along their
backbones. The parent strands cross over each other, but instead of
rejoining with the opposing parent strands, they rejoin with the
opposing daughter strands. Each daughter strand is a replica of the
opposing parent strand, so those strands travel in the same direction.
Therefore, Delbrück states, when the parent strands attach to the
opposite daughter strands, the parent strands attach in the right
direction. The successful rejoining of DNA strands in the method that
Delbrück describes can only occur if the daughter DNA strands started
replicating first. The process continues throughout the entire DNA
molecule, with each break occurring at each twist of the two parent DNA
strands.

Following the description of his suggested alternative
replication mechanism, Delbrück discusses why his mechanism is
energetically favorable. Though not explicitly stated by Delbrück,
chemicals are more likely to undergo a chemical change if less energy is
required to achieve that change. When DNA strands separate and
replicate, they undergo a chemical change that requires energy. In his
article, Delbrück argues that his DNA replication mechanism requires the
least amount of energy, so his mechanism is most likely to occur.
Delbrück postulates that breaking and rejoining DNA strands results in a
net zero energy consumption. He also argues that no work needs to be
done to correctly coil the daughter DNA strands, because those strands
are automatically coiled as they are produced. Delbrück continues his
discussion by stating that at any given time during replication, only
one small part of the entire DNA molecule is disrupted. The rest of the
molecule retains its stable, helical configuration. In contrast, if both
strand of DNA were separated before replication as Watson and Crick
suggested, the entire molecule would be unstable. According to Delbrück,
the benefits of minimal disruption in the DNA molecule are twofold.
First, the total energy use during the process is minimized. Second,
only a small part of the DNA molecule needs to be uncoiled, allowing the
process to occur in the tight constraints of a cell nucleus.

The final
section of "On the Replication" consists of a discussion of possible
experimental results that would indicate that Delbrück's replication
mechanism occurs in DNA. When Delbrück published the article, there was
no experimental evidence about how DNA replicated. To craft an
experimental method that would work, Delbrück first establishes that
because of how parental DNA strands cross over and join with daughter
DNA strands during his suggested replication mechanism, the final
daughter DNA molecules would consist of alternating parental and
daughter segments, thereby distinguishing the mechanism from other DNA
replication mechanisms. Delbrück hypothesizes that in his mechanism if
the parent DNA double helix could be labeled in some way and
differentiated from newly replicated DNA, the amount of labeled and
unlabeled DNA would remain equal in each new DNA double helix over many
replications. Delbrück notes that other scientists had tried to label
DNA by incorporating radioactive phosphorus into DNA, but were
unsuccessful. Delbrück concludes his article with a brief summary.

Delbrück's dispersive replication, presented in "On the Replication,"
provided a plausible counterexample to the semi-conservative model of
replication. While many accepted the Watson-Crick replication mechanism
initially, Delbrück's article showed that questions regarding DNA
replication were far from answered. In a book by historian of science
Frederic Lawrence Holmes about the study of DNA replication in the
1950s, Meselson, Stahl, and the Replication of DNA: A History of "The
Most Beautiful Experiment in Biology," Holmes credits Delbrück with
being the first to formally outline the issues surrounding DNA
replication. Like Watson and Crick's semi-conservative model, Delbrück's
dispersive replication model served only as theoretical speculation.
However, as Holmes emphasizes, Delbrück provided a way to find concrete,
experimental evidence supporting one model or the other.

Through his
publication of "On the Replication" and afterwards, Delbrück
participated in the DNA replication debate during the years leading up
to the Meselson-Stahl experiment. After Delbrück suggested his
alternative model, other scientists provided their own theories for how
DNA replicated that challenged the semi-conservative model. Some of
those scientists even communicated with Delbrück directly regarding
their ideas. Watson also communicated with Delbrück privately about DNA
replication after the article's publication. According to Holmes, the
large response to Delbrück's article prompted Watson to question his own
model of DNA and suggest counter theories to his own replication
mechanism.

Between 1957 and 1958, Meselson and Stahl applied the DNA
labeling method suggested by Delbrück in "On the Replication" to their
own experiment. Meselson and Stahl labeled parent DNA strands and then
traced the distribution of parental and daughter DNA over many
replication cycles. They found that DNA replicated semi-conservatively
as suggested by Watson and Crick.

Scientists used the understanding of
how DNA replicates to explain how heritable traits are carried and
passed down from generation to generation. In "On the Replication of
Desoxyribonucleic Acid (DNA)," Delbrück initiated a discussion aimed at
explaining the intricacies of DNA replication and experimentally
supporting a particular theory about how DNA stores and carries genetic
information. Through that debate, scientists learned how DNA replicates
to preserve and pass along the information contained within it.